The phase 3 iNNOVATE trial finds ibrutinib in combination with rituximab to be safe and effective in relapsed/refractory and treatment-näive patients with Waldenström’s macroglobulinemia.
At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, researchers reported positive findings from the phase 3 iNNOVATE trial, which assessed the safety and efficacy of the investigational use of ibrutinib (IMBRUVICA) in combination with rituximab in relapsed/refractory and treatment-naïve patients with Waldenström macroglobulinemia. The findings were also published in the The New England Journal of Medicine.
Ibrutinib works to block the protein, Bruton’s tyrosine kinase (BTK), which prevents the transmission of signals that cause B cells to mature and make antibodies, thus starving cancer cells and preventing them from multiplying and migrating. Ibrutinib was approved by the US Food and Drug Administration (FDA) last year.
Waldenström macroglobulinemia is a rare and incurable form of non-Hodgkin Lymphoma.
In an exclusive interview with Rare Disease Report®, an investigator for the iNNOVATE trial, Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, in Athens, Greece, commented on the study’s results.
“The combination of ibrutinib with rituximab is becoming a new standard of care that will allow a high percentage of patients with Waldenström macroglobulinemia to respond to treatment and have a prolonged progression-free survival,” he said. “I believe these results are very relevant for the treatment of patients with this rare disease.”
The study’s primary endpoint, a clinically and statistically significant difference in progression-free survival (PFS) for patients treated with ibrutinib in combination with rituximab versus those who were administered placebo plus rituximab, was met.
In the trial, 150 treatment-naive Waldenström macroglobulinemia patients were randomized to be administered ibrutinib 420 mg or placebo once-daily for 4 consecutive weeks followed by a second once-weekly for 4 consecutive weeks course of rituximab after a 3-month interval. Until disease progression or unacceptable toxicity, all patients were administered either IMBRUVICA 420 mg or placebo once daily continuously.
Over the course of the trial, it was observed that, compared with the placebo plus rituximab (hazard ratio, 0.20; confidence interval: 0.11-0.38, P <0.0001), ibrutinib in combination with rituximab significantly diminished the risk of disease progression or death by 80%. Secondary endpoints also supported the primary endpoint. They included the response rate, time to next treatment (TTnT), rate of sustained hemoglobin improvement, and the number of participants with adverse events (AEs).
Ibrutinib in combination with rituximab improved the PFS compared with the placebo plus rituximab with PFS rates of 82% versus 28% at 30 months, respectively, at a median follow-up of 26.5 months. The combination also notably prolonged PFS in all relevant subgroups, including treatment-naïve (HR, 0.34; CI: 0.12-0.95), relapsed (HR, 0.17; CI: 0.08-0.36), and in patients with MYD88L265P and CXCR4WHIM mutations (HR, 0.24; CI: 0.09-0.66) versus rituximab alone.
Additionally, ibrutinib in combination with rituximab exhibited significantly higher overall response rates and major response rates compared with the placebo plus rituximab (92% vs 47%; 72% vs 32% [both P <0.0001]). An improvement in hemoglobin was also observed in patients administered the combination versus the placebo plus rituximab arm (73% vs 41%, P <0.0001).
Seventy-five percent of the subjects on the combination treatment continued with the treatment at the time of analysis; however, TTnT was not obtained for ibrutinib in combination with rituximab and 18 months for placebo plus rituximab (HR, 0.096; P <0.0001). Ninety-four percent versus 92% were the 30-month OS rates in the two arms. At 25.8 months, which was the median time on the treatment combination, grade 3 or higher treatment-emergent AEs occurred in 60% of patients treated with ibrutinib plus rituxumab, versus 61% of patients treated with placebo plus rituxmab (15.5 months). In 43% versus 33% of patients on ibrutinib in combination with ritxuimab versus placebo plus rituximab, serious AEs occurred.
However, in the ibrutinib plus rituximab arm, no fatal AEs occurred, while 3 fatal AEs occurred in the placebo plus rituximab arm. With ibrutinib in combination with rituximab compared with placebo plus rituximab, meaningful reductions were observed in any grade immunoglobin M flare (8% vs 47%) and grade 3 or higher infusion reactions (1% vs 16%).
In another exclusive interview, Rare Disease Report® also sat down with Mark Wildgust, PhD, vice president of Medical Affairs Oncology at Janssen, to further discuss the trial’s positive results (see video).
Janssen had submitted a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) based on this data in the hopes of expanding the use of ibrutinib as a combination therapy in Waldenström macroglobulinemia.
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